Bone marrow failure syndrome-2 is an autosomal recessive disorder characterized by trilineage bone marrow failure, learning disabilities, and microcephaly. Cutan...
Bone marrow failure syndrome-2 is an autosomal recessive disorder characterized by trilineage bone marrow failure, learning disabilities, and microcephaly. Cutaneous features and increased chromosome breakage are not features (Tummala et al., 2014).
For a discussion of genetic heterogeneity of BMFS, see BMFS1 (614675).
▼ Clinical Features
Tummala et al. (2014) reported 2 unrelated patients, each born of consanguineous parents, with a bone marrow failure syndrome. The patients presented at ages 12 and 19 years, respectively. Each had trilineage bone marrow failure with hypocellular bone marrow. Bone marrow of 1 patient showed dysplasia. Both patients also had microcephaly and learning difficulties. One had abnormal facies and ear anomalies, and the other had hypotonia in infancy. Neither had mucocutaneous features or chromosomal breakage. One patient had shortened telomeres.
Zhang et al. (2016) reported an adolescent male, born of consanguineous parents, who presented with mild bone marrow failure and microcephaly without the typical Fanconi anemia (see 227650) phenotype. The patient's cells showed increased sensitivity to ionizing radiation and to phleomycin, suggesting a defect in DNA double-strand break (DSB) repair.
The transmission pattern of BMFS2 in the family reported by Tummala et al. (2014) was consistent with autosomal recessive inheritance.
▼ Molecular Genetics
By exome sequencing of 2 unrelated patients with bone marrow failure syndrome, Tummala et al. (2014) identified 2 different homozygous truncating mutations in the ERCC6L2 gene (R655X, 615667.0001 and c.1236_1239del, 615667.0002). Fluorescence labeling of patient cells showed that the mutant truncated proteins were mislocalized to the endoplasmic reticulum, autophagic vacuoles, and lysosomes, suggesting that normal localization was impaired by aggregation of the mutant protein and retention for degradation. Tummala et al. (2014) noted that a DNA-damage response mediated by ERCC6L2 is required during cell proliferation and tissue maintenance, and suggested that the mutations resulted in an increase in reactive oxygen species and the accumulation of DNA damage in cells, which underlie the disease manifestations observed in the affected individuals.
By linkage analysis and whole-exome sequencing in an adolescent male with bone marrow failure syndrome, Zhang et al. (2016) identified homozygosity for the previously reported R655X mutation in the ERCC6L2 gene. The mutation affected both the ERCC6L2 short isoform and the ERCC6L2 long isoform, HEBO. Transduction of wildtype HEBO complemented the DNA DSB repair defect in the patient's fibroblasts, whereas transduction of wildtype ERCC6L2 short isoform had no effect. Zhang et al. (2016) concluded that truncation of HEBO due to the R655X mutation caused the DNA DSB repair defect in the patient's cells.